Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Critical role of cyclin D3 in TSH-dependent growth of thyrocytes and in hyperproliferative diseases of the thyroid gland

Oncogene volume 22, pages 7576–7586 (2003)Cite this article

Abstract

We report that cyclin D3 is rate limiting for G1 progression in thyroid follicular cells and that its constitutive upregulation by chronic stimulation of the TSH/cAMP pathway plays a role in human and experimental hyperproliferative diseases of the thyroid gland. These conclusions are supported by in vitro and in vivo studies. In rat thyrocytes (PC Cl 3 cells), cyclin D3 expression is enhanced in response to activation of the TSH/cAMP pathway. Interference with the expression of G1 cyclins (in particular cyclin D3) by the antisense methodology strongly reduced TSH-dependent proliferation of PC Cl 3 cells, indicating that proper progression through G1 requires cyclin D3. Accordingly, PC Cl 3 cells engineered to overexpress cyclin D3 (PC-D3 cells) show enhanced growth rate and elude hormone-dependence and contact inhibition. Using an animal experimental model of thyroid stimulation, we demonstrate that cyclin D3 is a key mediator of TSH-dependent proliferation of thyroid follicular cells also in vivo. Cyclin D3 protein levels were higher in the thyrocytes from glands of propylthiouracil-treated rats compared with control animals. The increase in cyclin D3 expression occurred after the propylthiouracil-induced increase in TSH levels and preceded the burst of cell proliferation. Finally, we found that cyclin D3 protein is expressed in a fraction of human goiters but it is strongly overexpressed in most follicular adenomas.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Baldassarre G, Belletti B, Bruni P, Boccia A, Trapasso F, Pentimalli F, Barone MV, Chiappetta G, Vento MT, Spiezia S, Fusco A and Viglietto G . (1999). J. Clin. Invest., 104, 865–874.

  • Berlingieri MT, Akamizu T, Fusco A, Grieco M, Colletta G, Cirafici AM, Ikuyama S, Kohn L and Vecchio G . (1990). Biochem. Biophys. Res. Comm., 173, 172–178.

  • Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, Reed S, Sicinski P, Bartek J and Eilers M . (1999). EMBO J., 18, 5321–5333.

  • Carneiro C, Alvarez CV, Zalvide J, Vidal A and Dominguez F . (1998). Oncogene, 16, 1455–1465.

  • Coppee F, Depoortere F, Bartek J, Ledent C, Parmentier M and Dumont JE . (1998). Oncogene, 17, 631–641.

  • Corvilain B, Van Sande J, Dumont JE and Vassart G . (2001). Clin. Endocrinol., 55, 143–158.

  • Davies T, Marians R and Latif R . (2002). J. Clin. Invest., 110, 161–164.

  • Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP and Dremier S . (1998). J. Cell Biol., 140, 1427–1439.

  • Dremier S, Coulonval K, Perpete S, Vandeput F, Fortemaison N, Van Keymeulen A, Deleu S, Ledent C, Clement S, Schurmans S, Dumont JE, Lamy F, Roger PP and Maenhaut C . (2002). Ann. N. Y. Acad. Sci., 968, 106–121.

  • Dumont JE, Lamy F, Roger P and Maenhaut C . (1992). Physiol. Rev., 72, 667–697.

  • Ekholm SV and Reed SI . (2000). Curr. Opin. Cell Biol., 12, 676–684.

  • Florio T, Arena S, Thellung S, Iuliano R, Corsaro A, Massa A, Pattarozzi A, Bajetto A, Trapasso F, Fusco A and Schettini G . (2001). Mol. Endocrinol., 15, 1838–1852.

  • Fusco A, Berlingieri MT, Di Fiore PP, Portella G, Grieco M and Vecchio G . (1987). Mol. Cell. Biol., 7, 3365–3370.

  • Hedinger C, Willians ED and Sobin LH . (1993). International Histological Classification of Tumours, World Health Organization. 2nd edn. Springer-Verlag: Berlin, Heidelberg, New York, London, Paris, Tokyo.

    Google Scholar 

  • Herzinger T and Reed SI . (1998). J. Biol. Chem., 273, 14958–14961.

  • Kimura T, Dumont JE, Fusco A and Golstein J . (1999). Eur. J. Endocrinol., 140, 94–103.

  • Kimura T, Van Keymeulen A, Golstein J, Fusco A, Dumont JE and Roger PP . (2001). Endocr. Rev., 22, 631–656.

  • Ledent C, Dumont JE, Vassart G and Parmentier M . (1992). EMBO J., 11, 537–542.

  • Medina DL, Velasco JA and Santisteban P . (1999). Endocrinology, 140, 87–95.

  • Medina DL and Santisteban P . (2000). Eur. J. Endocrinol., 143, 161–718.

  • Morgan DO . (1995). Nature, 374, 131–134.

  • Pedrinola F, Rubio I, Santos CL and Medeiros-Neto G . (2001). Thyroid, 11, 15–20.

  • Perez-Roger I, Kim SH, Griffiths B, Sewing A and Land H . (1999). EMBO J., 18, 5310–5320.

  • Rognoni JB, Penel C and Ducret F . (1984). Acta Endocrinol., 105, 40–48.

  • Saiz AD, Olvera M, Rezk S, Florentine BA, McCourty A and Brynes RK . (2002). J. Pathol., 198, 157–162.

  • Sato K, Yamazaki K, Shizume K, Kanaji Y, Obara T, Ohsumi K, Demura H, Yamaguchi S and Shibuya M . (1995). J. Clin. Invest., 96, 1295–1302.

  • Shaughnessy Jr J, Gabrea A, Qi Y, Brents L, Zhan F, Tian E, Sawyer J, Barlogie B, Bergsagel PL and Kuehl M . (2001). Blood, 98, 217–223.

  • Sherr CJ and Roberts JM . (1999). Genes Dev., 13, 1501–1512.

  • Smeds S and Wollman SH . (1983). Lab. Invest., 48, 285–291.

  • Sonoki T, Harder L, Horsman DE, Karran L, Taniguchi I, Willis TG, Gesk S, Steinemann D, Zucca E, Schlegelberger B, Sole F, Mungall AJ, Gascoyne RD, Siebert R and Dyer MJ . (2001). Blood, 98, 2837–2844.

  • Wollman SH, Herveg JP, Zeligs JD and Ericson LE . (1978). Endocrinology, 103, 2306–2314.

  • Viglietto G, Romano A, Manzo G, Chiappetta G, Paoletti I, Califano D, Galati MG, Mauriello V, Bruni P, Lago CT, Fusco A and Persico MG . (1997). Oncogene, 15, 2687–2698.

  • Viglietto G, Califano D, Bruni P, Baldassarre G, Vento MT, Belletti B, Fedele M, Santelli G, Boccia A, Manzo G, Santoro M and Fusco A . (1999). Eur. J. Endocrinol., 140, 597–607.

  • Weinberg RA . (1995). Cell, 81, 323–330.

  • Wilson JD and Foster DW . (1989). The Thyroid. Textbook of Endocrinology, 7th ed. Press of Saunders Company: Philadelphia, USA.

    Google Scholar 

  • Wynford-Thomas D, Stringer MJ and Williams ED . (1982). J. Endocrinol., 94, 131–140.

  • Yamamoto K, Hirai A, Ban T, Saito J, Tahara K, Terano T, Tamura Y, Saito Y and Kitagawa M . (1996). Endocrinology, 137, 2036–2042.

Download references

Acknowledgements

This work was supported by the Progetto Finalizzato ‘Biotecnologie’ del CNR to GV and from Associazione Italiana Ricerca sul Cancro (AIRC) and Ministero dell'Istruzione e Ricerca Scientifica (MIUR) to AF. We are indebted to Jean Ann Gilder for editing the text.

Author information

Authors and Affiliations

  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘L.Califano’, Università Federico II, via S Pansini 5, Naples, 80131, Italy

    Maria Letizia Motti, Angelo Boccia, Letizia Cito, Gustavo Baldassarre & Alfredo Fusco

  2. Servizio Oncologia Sperimentale E, Istituto Nazionale Tumori, via M Semmola, Naples, 80131, Italy

    Barbara Belletti, Mario Monaco & Gennaro Chiappetta

  3. Dipartimento di Biochimica e Biotecnologie Mediche, Università ‘Federico II’, via S Pansini 5, Naples, 80131, Italy

    Paola Bruni

  4. Dipartimento di Scienze Morfologiche e Funzionali, Facoltà di Medicina e Chirurgia, Università Federico II, via S Pansini 5, Naples, 80131, Italy

    Giancarlo Troncone & Lucio Palombini

  5. Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘L.Califano’, Università Federico II, via S Pansini 5, Naples, 80131, Italy

    Giuseppe Viglietto

Authors
  1. Maria Letizia Motti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Angelo Boccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara Belletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paola Bruni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giancarlo Troncone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Letizia Cito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mario Monaco
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gennaro Chiappetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gustavo Baldassarre
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lucio Palombini
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alfredo Fusco
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Giuseppe Viglietto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giuseppe Viglietto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Motti, M., Boccia, A., Belletti, B. et al. Critical role of cyclin D3 in TSH-dependent growth of thyrocytes and in hyperproliferative diseases of the thyroid gland. Oncogene 22, 7576–7586 (2003). https://doi.org/10.1038/sj.onc.1207055

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207055

Keywords

This article is cited by

Search

Advanced search

Quick links